Sei-1 promotes double minute chromosomes formation through activation of the PI3K/Akt/BRCA1-Abraxas pathway and induces double-strand breaks in NIH-3T3 fibroblasts.

Cell Death Dis. 2018 Mar 01;9(3):341

Xing Tian ¹ , Chang Liu ¹ , Xin Wang ² , Fei Wang ¹ , Liqun Wang ¹ ,

Xing Tian ¹ , Chang Liu ¹ , Xin Wang ² , Fei Wang ¹ , Liqun Wang ¹ , Lu Xu ¹ , Jinfa Ma ¹ , Yating Gao ¹ , Yantao Bao ¹ , Falin Wang ³ , Luyao Sun ¹ , Junni Wei ¹ , Chuwen Lin ¹ , He Zhang ¹ , Gang Zhu ¹ , Xinyuan Guan ⁴ , Songbin Fu ⁵ , Chunyu Zhang ⁶

+ et al

Author information

¹ Laboratory of Medical Genetics, Harbin Medical University, 150081, Harbin, China.
² The Department of Otolaryngology, Heilongjiang provincial hospital, 150081, Harbin, China.
³ Obstetrics Department, Fourth Affliated Hospital, Harbin Medical University, 150081, Harbin, China.
⁴ Department of Clinical Oncology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
⁵ Key Laboratory of Medical Genetics, Harbin Medical University, Heilongjiang Higher Education Institutions, 150081, Harbin, China.
⁶ Laboratory of Medical Genetics, Harbin Medical University, 150081, Harbin, China. zhangcy@ems.hrbmu.edu.cn.

摘要

Sei-1 is a potential oncogene that plays an important role in promoting genomic instability. Double minute chromosomes (DMs) are hallmarks of gene amplification and contribute to tumorigenesis. Defects in the DNA double-strand break (DSB) repairing pathways can lead to gene amplification. To date, the mechanisms governing the formation of DMs induced by Sei-1 are not fully understood. We established DMs induced by Sei-1 in the NIH-3T3 cell line. RNA-sequencing was used to identify key characteristics of differentially expressed genes. Metaphase spreads were used to calculate DM numbers. Immunofluorescence was employed to detect Î³H2AX foci. Western blot and Akt pathway inhibition experiments were performed to reveal the role of the PI3K/Akt/BRCA1-Abraxas pathway in Sei-1-induced DMs. Luciferase reporter assay was employed to explore the regulatory mechanisms between Sei-1 and BRCA1. DM formation was associated with a deficiency in DSB repair. Based on this finding, activation of the PI3K/Akt/BRCA1-Abraxas pathway was found to increase the DM population with passage in vivo, and inhibition resulted in a reduction of DMs. Apart from this, it was shown for the first time that Sei-1 could directly regulate the expression of BRCA1. Our results suggest that the PI3K/Akt/BRCA1-Abraxas pathway is responsible for the formation of DMs induced by Sei-1.

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